Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Hospital at Solna, Stockholm, Sweden.
PLoS One. 2009 Nov 10;4(11):e7773. doi: 10.1371/journal.pone.0007773.
Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and nerve loss in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate complex pathogenic mechanisms. Transcriptional control through isoform selection and mRNA levels determines pathway activation and ultimately susceptibility to disease.
METHODOLOGY/PRINCIPAL FINDINGS: We have studied the role of alternative splicing and differential expression in lymph node cells from EAE-susceptible Dark Agouti (DA) and EAE-resistant Piebald Virol Glaxo.AV1 (PVG) inbred rat strains using Affymetrix Gene Chip Rat Exon 1.0 ST Arrays. Comparing the two strains, we identified 11 differentially spliced and 206 differentially expressed genes at day 7 post-immunization, as well as 9 differentially spliced and 144 differentially expressed genes upon autoantigen re-stimulation. Functional clustering and pathway analysis implicate genes for glycosylation, lymphocyte activation, potassium channel activity and cellular differentiation in EAE susceptibility.
CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that alternative splicing occurs during complex disease and may govern EAE susceptibility. Additionally, transcriptome analysis not only identified previously defined EAE pathways regulating the immune system, but also novel mechanisms. Furthermore, several identified genes overlap known quantitative trait loci, providing novel causative candidate targets governing EAE.
多发性硬化症（MS）是一种慢性炎症性疾病，导致中枢神经系统脱髓鞘和神经丧失。实验性自身免疫性脑脊髓炎（EAE）是 MS 的动物模型，广泛用于研究复杂的发病机制。通过异构体选择和 mRNA 水平的转录控制决定了途径的激活，最终决定了对疾病的易感性。
方法/主要发现：我们使用 Affymetrix Gene Chip Rat Exon 1.0 ST Arrays 研究了易发性 Dark Agouti（DA）和抗性 Piebald Virol Glaxo.AV1（PVG）近交系大鼠淋巴结细胞中可变剪接和差异表达在实验性自身免疫性脑脊髓炎（EAE）中的作用。将这两个品系进行比较，我们在免疫后第 7 天鉴定出 11 个差异剪接和 206 个差异表达的基因，以及在自身抗原再刺激时鉴定出 9 个差异剪接和 144 个差异表达的基因。功能聚类和途径分析表明，糖基化、淋巴细胞激活、钾通道活性和细胞分化的基因与 EAE 易感性有关。
结论/意义：我们的结果表明，可变剪接发生在复杂疾病中，可能控制着 EAE 的易感性。此外，转录组分析不仅鉴定了以前定义的调节免疫系统的 EAE 途径，还鉴定了新的机制。此外，几个鉴定出的基因与已知的数量性状基因座重叠，为控制 EAE 的新的致病候选靶点提供了依据。
